All right. Good morning, everyone. Welcome to our Fireside Chat with Affimed. I'm Li Watsek, a biotech analyst at Cantor, and today I'm very pleased to have CEO Shawn Leland and CMO Andreas Harstrick with us. W elcome both. I guess to start off, Shawn, maybe you can give us an overview of Affimed, what you guys are working on, and what's coming up.
Thanks, Li. Affimed is a company on developing NK cell engagers. We have three programs in clinical development. All three of those programs now have clinical proof of concept, either as a monotherapy or in combination. You know, Our most advanced program is called AFM13 or acimtamig.
This is a CD30 NK cell engager program, which is currently in a combination study with allo-NK cell therapy. We just presented data on 12 patients, showing an 83% overall response rate, 50% CR rate. We'll have additional data coming in Q4 of this year on that program. Our second most advanced program is AFM24. This is a EGFR NK cell engager. We're studying this program in combination with anti-PD-L1.
This program is being studied in non-small cell lung cancer, both in patients with EGFR wild-type as well as patients with EGFR mutations. We've also shown compelling data in both of those patient populations, you know, showing north of a 20% overall response rate and a median PFS that's currently around five-plus months, which is quite encouraging in the context of other agents that are used for these indications. The last and final program is AFM28. This is a CD123 NK cell engager program. This program also has demonstrated some encouraging monotherapy activity. We just recently presented data on six patients.
Three out of those six patients had a complete response or a complete response with incomplete hematologic recovery, showing a 50% CRR rate, which is also quite compelling in the context of other therapies. You would expect about a 10% to 30% CRR rate in this patient population.
Okay, great. Thanks for that overview. I guess before we dive into your three clinical programs, just sort of wondering, where do you see the NK cell engagers playing in the context relative to T cell engagers? I mean, do you think you guys really need, you know, combinations to really achieve a sufficient level of efficacy?
Overall, you know, I think this field of NK cell engagers is quite encouraging. W hat's unique is really the tumor specificity that exists for these NK cell engager approaches. They tend to have a wider therapeutic index in comparison to T cell engager approaches.
The other significant advantage with the NK cell engager approach is that we have not seen cross-resistance across other therapeutic modalities. W e've seen activity post small molecules with programs like AFM24, for example. You know, we've seen activity, you know, post-CAR T with the CD30 approach. T hese are probably the two most compelling aspects that I feel like are differentiating from NK cell engager platforms. You know, you kind asked the question about, you know, is it necessary to have combination?
We've seen both monotherapy as well as combination activity with these approaches. So we do see compelling monotherapy activity. We also do see additivity and synergy with other agents as well.
Okay, maybe let's talk about your lead program, the AFM13, the CD30 ICE, molecule first. Obviously, you have shown some pretty nice data from prior study at MD Anderson. M aybe just walk us through, you know, the regimen I believe you're combining with NK cells.
What those data show before you sort of move into the phase two.
Andreas, you wanna take this question?
Happy to do so. Y ou referenced to the really groundbreaking data that we have shown when we combine our CD30 ICE with allogeneic NK cells in the MD Anderson study in 36 patients with Hodgkin lymphoma, who were completely refractory to any treatments, refractory to chemotherapy, refractory to PD-1, refractory to ADCETRIS. We achieved a 95+% overall response rate. We achieved a 70+% complete response rate.
I think what's more important is, in our updated presentation, we can show that these responses are really clinically meaningful. About one-third of the patients, when we did the last data cutoff, had an ongoing complete response at 12 months, and we have seen patients with ongoing complete responses at 18 and 24 months. This really would change the paradigm, how you can treat refractory Hodgkin lymphoma.
Now, the limitation here was that we generated this data with an academic NK cell that could not be produced in industrial qualities and quantities, so we had to change. We are now combining with a commercially available or commercially suitable NK cell product that can be produced in large quantities, can be cryopreserved.
I n our study, we made some changes. Of course, we changed the NK cell. We changed the way how we administer. We are not pre-complexing anymore, we are co-administrating, and we have really moved to a multicenter trial. T he data we have seen from this new study are really for me, really extremely compelling. We see, as Shawn said, an 83% overall response rate. We see over 50% complete responses, and we see this in a real-world setting.
We have multiple sites contributing. We have 10 sites who meanwhile have contributed patients, again, very heavily completely refractory patients. Our intention is to continue this study. We believe, and this is somehow confirmed with our discussions with FDA, that FDA considers that there is no standard of care for these heavily pretreated patients, and therefore, a single-arm study could be a basis for an accelerated approval, so no need for a comparative arm at this point in time.
Recruitment has gone very well. We disclosed the first data of the first 12 patients at our last earnings call. We have also said we have now completed enrollments into cohort 3 and 4, which will enable us to give a very meaningful update on this first 4 cohorts at an upcoming meeting towards the end of the year.
Okay. M aybe let's focus on your phase II, potentially, pivotal study here. I wonder if you can just talk a little bit about the trial design. I believe you have four cohorts right now, and you're going into a different phase. M aybe just walk us through the design. Y ou mentioned that you've shown data from cohort one and two. Maybe you can talk a little bit about, you know, cohort three and four.
In this trial, because we wanted to design a registration-relevant trial, we are addressing several aspects that are important for FDA. W e initially have four cohorts, as you said. In these four cohorts, we are evaluating two different doses of acimtamig, and we are also evaluating two different doses of the NK cell.
The data that I was just referring to was the 83% response rate were achieved with the lower dose of NK cells. In cohort three and four, we will now increase even the number of NK cells. In the second step, we will look at two of these four different dose permutations to address FDA's request of gathering data for a dose response and dose-effect relationship. W e are here working towards Project Optimus. And then this is a another step of roughly 26 patients.
We will continue one of these two doses to generate a data set of roughly eighty response evaluable patients, which we feel, given the magnitude of the effect and the differentiation over what is currently available, should be the basis for an accelerated approval.
Excellent. I wonder if you can put the data into context for us. Obviously, these are pretty, you know, late-line patients, and you've seen pretty nice response rate and CR rate. I guess what should be the right benchmark here?
I think to put this data into perspective, in our MD Anderson data set, we really looked at the response of each individual patient, that this patient had to the last preceding therapy. The response rate was zero.
There is no treatment for these patients, and all these patients came from really prestigious lymphoma centers. You would have to assume that all these doctors really tried to do the best for their patients, still did not get a single response. With our approach, we got 97% responses. When we talk to key opinion leaders, they constantly tell us anything that produces a 50% response rate in this refractory patient population and a duration of responses or a PFS of roughly six months would be a significant step ahead in these patients.
Again, if you put this into perspective with the over 90% response rate seen at MD Anderson, with 85% response rate that we see now, and the mature PFS data at MD Anderson indicating that one-third of patients live longer than a year, we feel very comfortable that we have a significant safety margin to fulfill the requirements for an initial approval.
Now, I wanted to talk a little bit about, you know, durability, duration of response, and I think that's a question we hear from investors as well, especially for NK cells, which is how durable the efficacy is. Obviously, your current data is still sort of immature, we don't know what the DOR is. I n terms of the trends that you are seeing, I wonder if you can give us some color there. Is it going the right way? A lso, what should be the bar here? Is it six months? Is it eight months? How should we think about that?
Again, we have to look across our programs. What we hear in the Hodgkin setting, refractory patient population, six months is basically the benchmark where most of the Hodgkin lymphoma experts would start to use such therapy and would feel that this is a significant improvement in terms of durability of responses or tumor control with NK cell-based therapies in general.
I think there is a certain misconception which comes from some studies where allogeneic NK cells were used, and there was persistence of these NK cells followed, which is shorter than with CAR-T cells. Now, what we clinically see, and this is not only with our NK cell programs, also with our combination approaches in non-small cell lung cancer, with our single agent, that if you activate the patient's own NK cells, which is especially in the solid tumors, you can produce very, very durable responses.
If you recall our data in non-small cell lung cancer, EGFR wild-type, all of our responses were ongoing in excess of seven months, and we had patients out when we reported last data last time, eight, nine, and 10 months in ongoing response. What we published now in our EGFR-mutant non-small cell lung cancer cohort, again, responses, all responses on treatment for more than seven months.
If you benchmark this against standard of care, for example, EGFR wild-type, pretreated with platinum, PD-1, which is a frequently used treatment regimen, PD-1 in these patients produces a PFS of 2.8 months. So now take our 7, 6.5-7 months compared to 2.8. Even the most effective therapy for refractory non-small cell lung cancer, which currently would be docetaxel plus a VEGF inhibitor, gives you a response, a progression-free survival of roughly 4 months.
R ecent data now published at the World Lung Cancer Conference, even this, I would say, a little bit hyped ADCs, Trop-2 or two or three ADCs. When you look at the PFS, again, the randomized phase 3 study was a Trop-2 ADC, PFS 4.3 months.
We believe that especially when you utilize the crosstalk between NK cells and T cells, which we are utilizing in our non-small cell lung cancer studies, you can produce very meaningful durable responses and very competitive PFS.
That's a great point, and we're gonna talk about the EGFR program just in a bit. I guess going back to CD30, obviously, you're gonna have data update later this year from cohort three and four. You're using more NK cells, so I wonder if you can just set the expectations here. I mean, is it necessarily, you know, reasonable to expect higher efficacy with more NK cells, or that's not necessarily the case?
I think, if you look across the NK cell studies, increasing NK cell numbers, has, in some studies, resulted in higher efficacy. There appears to be a certain kind of ceiling effect, that if you go higher than the critical number, you're not gaining more.
We currently have to evaluate, whether we are still in the, ascending part of the dose response curve. There clearly is a possibility that with a higher NK cell number, you may even see better data than we have seen with our current lower NK cell number. But the caveat is, if you already have 83% responses. There's not an awful lot that you can improve.
You're almost at 100%.
That's a good point. You know, Andreas, you talked about, you know, potentially going to the FDA to get accelerated approval with a single-arm study. How should we think about a confirmatory study? What are some of the options that you guys are looking at?
I think there are a couple of options. I mean, we have to realize that refractory Hodgkin lymphoma is a disease of very high unmet medical need. And FDA has, in the past, already indicated that even maturation of data that are generated in a phase II study in a disease setting where there's no treatment alternative, may support full approval.
W e believe that there is a possibility to gain accelerated approval on early efficacy readouts, which would be response rate and PFS, and then with longer follow-up, and if you can demonstrate you have a meaningful proportion of patients who get into long-term survival or maybe even cured, that this would support the conversion into a full approval. The second option, which we have to look at, is to also incorporate this regimen, and this has a very benign safety profile.
Also important to say, so we do not see any cross toxicities compared to chemotherapy, PD-1. So we feel we can combine this approach with a lot of standard of care agents. So we also can think about strategies to incorporate this treatment into earlier lines of therapy and then create a randomized phase II/III, but in earlier lines of therapies.
For later lines of therapy, and this is again what FDA has confirmed, there is no standard of care. How do you enroll a patient in a study where you say, "With standard treatment, you have a 10% response rate. With our treatment, you have an 85% response rate?" You're not getting patients who feel that this is a good idea.
I guess, at which point you're going to the FDA to align on that confirmatory path? Like, do you have to wait for certain, you know, patients' number data to mature? Like, maybe just help us think through the timing of that and when we might get clarity.
I think one important point would be when we have our initial four cohorts, so 24, 25 patients, with a reasonable follow-up, which I would say should at least be three months, probably six months. This is a point where you can start to interact with FDA.
We believe also that our data from the first 24 patients would enable us to file for a breakthrough or an RMAT designation, and by this, you would be able to really not only interact with FDA at certain points, but you would have to have a continuous dialogue with FDA. What we have seen when we discussed our first of the LuminICE studies, it's a current study, there was a tremendous buy-in from FDA.
Close to 20 reviewers, and everybody was really actively contributing. W e think that FDA also feels that this is a very important treatment alternative we can create for patients.
I want to touch on the commercial opportunity here. Obviously, in Hodgkin Lymphoma, we got some pretty good therapies upfront. A lot of patients can be cured. H ow are you thinking about the opportunity in sort of later line? Obviously, you've shown very high response rate and, you know, CR rate, and potentially you can even put patients on stem cell transplant. M aybe talk a little bit about that.
I think, you know, as you look, you know, from a global perspective at the major markets, right? US, Japan, EU five, you know, there's approximately three thousand relapsed refractory patients with, you know, Hodgkin's lymphoma that, you know, are in this kind of third line, you know, plus setting. Andreas obviously just touched upon the ability to move into earlier lines.
We think that there's great potential there, and that would obviously expand the commercial opportunity. I think the other key aspect here is that there are obviously other CD30 positive driven hematologic malignancies, you know, such as PTCL. In PTCL, there's approximately, you know, five thousand patients per year in this relapsed refractory setting where we would initially start.
You're talking about, you know, approximately 8,000 patients globally, which, you know, we think would be a meaningful commercial opportunity as we think about being able to expand beyond Hodgkin's lymphoma into PTCL, and then also being able to potentially expand into earlier lines as well.
What about your partnership with Artiva? Talk a little bit about that.
The partnership with Artiva is focused on a clinical development collaboration. You know, we're obviously providing acimtamig, you know, they are providing the allo-NK cell. Y ou know, so we are essentially paying for the partnership in terms of the clinical development costs. Artiva does have, you know, obligations to co-chair in the event that there is a need to run a confirmatory trial, and as Andreas just alluded to, we're not sure whether that may or may not be the case.
Confirmatory data may be sufficient to be able to convert from an accelerated approval to a full approval in this setting.
I want to switch gears here to AFM24, which is your EGFR program. Andreas, you touched on some of the data you presented in non-small cell lung. I know you're gonna have a pretty big, you know, update later this year in wild type patients. M aybe just set the stage for us. What do you hope to show? W hat will be the bar for success?
As I said, we have two programs currently running for the EGFR targeting molecule. M aybe important to just highlight because there are EGFR TKIs, EGFR antibodies. The mechanism of action of AFM24 is fundamentally different. We are not impacting the signaling pathway, which is a target for both the TKIs as well as for the antibodies like ERBITUX or panitumumab.
We only use EGFR as a docking station to bring in the NK cells, and they do all the killing. W e have already demonstrated that none of the resistance-conferring mutations, whether it's downstream mutations like KRAS mutations, BRAF mutations, or mutations in the EGF receptor, confer any resistance to NK cells. W e are working across all resistant phenotypes. Now, what we have are data from two ongoing cohorts where we recruit patients with EGFR wild-type tumors.
These patients all have failed PD-1 and all have failed chemotherapy. We have another cohort where we recruit EGFR mutant patients. All these patients have failed TKI, and basically all patients have also failed chemotherapy. A gain, an area where there is basically no established standard of care. We are consistently seeing objective responses in both cohorts, roughly 22% to 25% objective responses. As I mentioned already, these responses seem to be very durable.
The EGFR wild-type cohort has a little bit longer follow-up. Here we published that the responses were lasting 8-9 months. I mportantly, also, all patients who responded had a documented progression on PD-1. T his is not explainable in any way with the PD-1 that we are using in combination.
EGFR mutant a little bit earlier, but again, the responses that we reported at the last earnings call were on therapy for a minimum of seven months. If you benchmark this, across both EGFR mutant and EGFR wild-type, again, PD-1 based therapies in this setting come up with a progression-free survival of roughly 2.5 months.
Chemotherapy, with or without VEGF, comes up with a progression-free survival of roughly 4-4.5 months. So we believe that if we can show, can produce data that indicate a progression-free survival of roughly 6 months or, north of 6 months, this is a significant improvement over what we can achieve with standard of care and could form the basis for a randomized phase 3 study with registrational intent.
A very important other distinguishing feature is that we achieve this data with a regimen that does not use any chemotherapy. And this is important, and I've been a medical doctor for more than a decade. If you have a patient who has gone through two lines of chemotherapy, at least one third of patients do not want any chemotherapy. So providing a very active regimen with a very good safety profile, chemotherapy-free, I think we have a very competitive asset set of assets here.
Great. I guess in the interest of time, let's just talk about your last program, AFM28, and obviously you show some pretty encouraging data in AML. Let me just rehash that, and what is sort of the plan there? Do you have a monotherapy path?
AFM28, here we are targeting CD123 on acute myeloid leukemia. That's a very important target, because we are not addressing only the leukemic blast, but also the leukemic stem cells. U nlike monoclonal antibodies, we have shown, even in patient samples, that we can really eradicate leukemic stem cells with very low CD123 expression.
Our monotherapy study has gone through six dose escalation steps, has shown, again, a very good safety profile. At a dose of 300 mg, we currently have six patients available. Again, all patients treatment refractory. We have seen three complete, or complete responses with incomplete hematologic recovery, so a 50% overall response rate, which we believe is very, very compelling. Again, small data set right now. Our immediate strategy is to extend these monotherapy data to really have a more robust signal.
Given the safety profile, we also think that combination with any kind of standard of care, like hypomethylating agents, venetoclax, could be a next step to, again, form a data set that ultimately can lead into a registration program. But I think early data, seeing three CRs out of six patients, for me, was unexpected, but is a very strong signal in my eyes.
Great. Thank you so much. Guess we'll wrap up here. Shawn and Andreas, thanks for a great discussion.
Thanks.
Thank you very much, Li.